During the past three years we performed a pharmacokinetically designed double-blind placebo-controlled study of nortriptyline in 5-12 year old subjects with DSM-III major depressive disorder (MDD), non-delusional type based on the hypothesis that children and adults have the same illness and therefore should have a similar response to treatment. However, midpoint analysis of our data (N=33) did not show a significant difference between the rate of response to active (N=18) or placebo (N=15) drug despite optimal plasma levels and excellent compliance. This raises the need to identify alternate hypotheses of the relationship between adult and pediatric depression and develop systematic studies to test them. The hypotheses we propose to test are: (1) that MDD subjects will have a heterogenous course (e.g. unipolar, bipolar, delusional) even though they were homogenous at baseline; (2) that the MDD subjects will have a poor prognosis similar to the poor outcome reported by Kovacs et al; (3) that the NT study subjects will not differ in rate of relapse from newly recruited MDD subjects; (4) that the psychosocial functioning of the affectively disordered subjects will be impaired compared to the normal controls. In order to test these hypotheses, we are proposing a five year prospective, blindly rated follow-up study of the NT study subjects and of two control groups. One of these would be a matched normal control group to permit comparison with age- appropriate functioning. The other would be newly recruited MDD subjects treated naturalistically to control for cohort effects and for participation in a drug protocol. One hundred subjects (50 NT study, 25 newly recruited MDD, 25 normals) would be followed with assessments every four months to enhance the likelihood of diagnosing manic or hypomanic episodes, which may be brief in children. The proposed study would provide families, practitioners and educators with much needed prognostic information. Further, it would provide investigators with the armamentaria needed to design future treatment studies aimed at more specific populations.